ES2298431T3 - FORMULATION OF GRANULES OF MONTELUKAST. - Google Patents

Abstract

A fluid and dispersible pharmaceutical composition, comprising granules comprising a pharmaceutically acceptable high fluidity substrate coated with montelukast sodium and a pharmaceutically acceptable lubricant.

Description

Montelukast granule formulation.

Background of the invention

Sodium montelukast (SINGULAIR®) is a leukotriene receptor antagonist approved for Asthma treatment in adult and pediatric patients from 2 year old. The drug is currently being studied for the seasonal allergic rhinitis treatment, as well as for a use potential in young children 6 months of age. The montelukast of sodium is currently available in the form of coated tablets with a 10 mg film for adults and chewable tablets of 4 mg and 5 mg for children.

Summary of the invention

The present invention relates to a new formulation of sodium montelukast in the form of granular powder that can be ingested or mixed with food or other edibles. The new formulation is suitable for use by patients who have difficulty swallowing or chewing tablets or who prefer not to
Cerlo.

Detailed description of the invention

The present invention provides a fluid and dispersible pharmaceutical composition comprising granules  which have a substrate coated with montelukast sodium and a lubricant. The granules of the present composition may be prepared by coating the substrate, optionally agglomerated in first with a pharmaceutically acceptable binder, with an aqueous solution of sodium montelukast. Drug granules resulting are dried and combined with a lubricant pharmaceutically acceptable to produce a fluid composition and dispersible suitable to be packaged.

In the present invention, the substrate can be whichever is pharmaceutically acceptable; normally used a sugar such as mannitol, sucrose, lactose, xylitol or the like. He substrate is preferably used in a form that is high fluidity, a feature that facilitates an exact dosage of the granules of the final product in unit dose sachets for Its distribution in the market. If the substrate is not high fluidity, it is necessary to agglomerate individual particles in the form of larger particles

In one embodiment of the granules, the substrate It is spray dried mannitol, which can be prepared by drying by spraying an aqueous solution of mannitol using procedures conventional. Spray dried mannitol available in the trade (for example, PEARLITOL® SD 200, Roquette Freres, France) It can also be used in the present invention. The particles Spray dried mannitol as PEARLITOL® SD 200 they are generally spherical, which gives this material its high fluidity property. Mannitol is preferably used due to its sweetness, refreshing taste and non-hygroscopic nature. The substrate normally comprises about 95 to approximately 98% by weight of the composition.

In cases where the substrate is very high fluidity by itself, can be used to produce drug granules without additional agglomeration or, optionally, The substrate can be agglomerated first with a binder pharmaceutically acceptable. Binders Pharmaceutically acceptable are for example hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose and polyvinylpyrrolidone. Agglomeration of the substrate particles is carried out by applying a solution aqueous binder on the substrate, for example, by spraying a solution of the binder on a fluidized bed of the substrate.  The binder, when used, normally comprises of about 2 to about 5% of the composition. The resulting agglomerated substrate particles are dried and used in The next stage.

The substrate particles are coated with montelukast sodium, for example, by spraying an aqueous solution of drug directly on a fluidized bed of the substrate for produce the drug granules. The granulation procedure gives rise to drug coated granules, which after drying are sized to provide granules smaller than approximately 850 micrometers The sized granules are combined with a lubricant and used to refill the container of the final product.

Sodium montelukast is a known compound and its preparation is described, for example, in US Pat. 5,565,473 and 5,614,632. To be used in the present invention, a solution of sodium montelukast in water is used in the granulation process. Montelukast normally comprises from about 0.4% to about 5% of the composition, so that each unit dose container contains the desired amount of montelukast sodium, which ranges in the range of about 2 mg to about 20 mg per
dose.

One skilled in the art will appreciate that they can other inert ingredients are added to the composition to confer on the final product desired properties such as flavor or appearance; for example, sweeteners such as aspartame, flavoring compounds and food coloring.

Dried and sized drug granules they are combined in a drum with a lubricant to facilitate the product flow during the filling operation of the forms of unit dosage, and to avoid the union of the components metal moving during this operation. Lubricants Suitable are pharmaceutically acceptable and include, without limitation, magnesium stearate, talc and the like. Lubricant usually comprises from about 0.25 to about 1% of the composition.

The lubricated granules are used to fill the final unit dose container, which must provide protection against light and moisture to the drug granules. An example of a suitable container is a sheet (for example, aluminum), bag or on. The sheet may be stratified with an external film of polyester that acts as a barrier resistant to children (bites and tears). A low polyethylene laminate internal linear density acts as the heat seal component for the sachets

Sodium montelukast is an antagonist of leukotriene receptors and as such can be used for treatment and prevention of diseases and disorders mid by leukotrienes. Leukotriene antagonists are useful in treatment of asthma, allergic rhinitis (including seasonal and perennial), atopic dermatitis, chronic urticaria, sinusitis, polyps nasal, chronic pulmonary obstruction disease, conjunctivitis, including rhinoconjunctivitis, migraine, cystic fibrosis and wheezing bronchiolitis secondary to viral (such as respiratory syncytial virus), among others.

For the treatment of asthma, this composition can be administered to patients by placement directly in the patient's mouth or by pre-mixing with a Soft food like applesauce and the like. The dose established montelukast for asthma is usually of approximately 10 mg per day for an adult, and for children of about 2 to about 5 mg per day. However, the dose magnitude may vary with nature and severity of the state to be treated and with the age, weight and response of the individual patient; a practitioner of ordinary experience in the technique will be able to adjust the normal dose upwards or descending to provide an adequate dose and a scheme of dosage based on individual characteristics and patient needs

For the treatment of allergic rhinitis (including seasonal and perennial), this composition may  be administered to patients by direct placement in the mouth of the patient, or by prior mixing with food as compote Apple and the like. The dose of montelukast for rhinitis Allergic is about 10 mg per day for an adult, and for Children from about 2 to about 5 mg per day. Without However, the magnitude of the dose may vary with the nature and the severity of the condition to be treated and with age, weight and individual patient response; a practitioner of experience ordinary in the art will be able to adjust the normal dose in ascending or descending direction to arrange an adequate dose and a dosage scheme based on the characteristics individual and patient needs.

For the treatment of atopic dermatitis, the This composition can be administered to patients by Direct placement in the patient's mouth, or by pre-mixing with foods like applesauce and the like. The dose of montelukast for atopic dermatitis can be approximately 10 mg per day for an adult and for children about 2 to approximately 5 mg per day. However, the magnitude of the dose may vary with the nature and severity of the state that is being treated and with the patient's age, weight and response individual; a practitioner of ordinary experience in the art will be able to adjust the typical dose upwards or descending to provide an adequate dose and a scheme of dosage based on individual characteristics and patient needs

For the treatment of chronic urticaria, the This composition can be administered to patients by Direct placement in the patient's mouth, or by pre-mixing with foods like applesauce and the like. The dose of montelukast for chronic urticaria can be approximately 10 mg per day for an adult and for children about 2 to approximately 5 mg per day. However, the magnitude of the dose may vary with the nature and severity of the state that is being treated and with the patient's age, weight and response individual; a practitioner of ordinary experience in the art will be able to adjust the typical dose upwards or descending to provide an adequate dose and a scheme of dosage based on individual characteristics and patient needs

For the treatment of sinusitis, the present composition can be administered to patients by placement directly in the patient's mouth, or by prior mixing with foods like applesauce and the like. The dose of montelukast for sinusitis can be approximately 10 mg per day for an adult and for children from about 2 to approximately 5 mg per day. However, the magnitude of the dose may vary with the nature and severity of the state that is being treated and with the patient's age, weight and response individual; a practitioner of ordinary experience in the art will be able to adjust the typical dose upwards or descending to provide an adequate dose and a scheme of dosage based on individual characteristics and patient needs

For the treatment of nasal polyps, the This composition can be administered to patients by Direct placement in the patient's mouth, or by pre-mixing with foods like applesauce and the like. The dose of montelukast for nasal polyps can be approximately 10 mg per day for an adult and for children of approximately 2 to approximately 5 mg per day. However, the magnitude of the dose may vary with the nature and severity of the state that is being treated and with the patient's age, weight and response individual; a practitioner of ordinary experience in the art will be able to adjust the typical dose upwards or descending to provide an adequate dose and a scheme of dosage based on individual characteristics and patient needs

For the treatment of obstruction disease Chronic pulmonary (COPD), the present composition may be administered to patients by direct placement in the mouth of the patient, or by pre-mixing with food as compote of Apple and the like. The dose of montelukast for COPD can be approximately 10 mg per day for an adult and for children of about 2 to about 5 mg per day. However, the dose magnitude may vary with nature and severity of the state being treated and with age, weight and response of the individual patient; a practitioner of ordinary experience in the technique will be able to adjust the typical dose in the direction ascending or descending to arrange an adequate dose and a Dosing scheme based on individual characteristics and The needs of the patient.

For the treatment of conjunctivitis (including rhinoconjunctivitis), the present composition can be administered to patients by direct placement in the patient's mouth, or by pre-mixing with foods such as applesauce and Similar. The dose of montelukast for conjunctivitis can be approximately 10 mg per day for an adult and for children of about 2 to about 5 mg per day. However, the dose magnitude may vary with nature and severity of the state being treated and with age, weight and response of the individual patient; a practitioner of ordinary experience in the technique will be able to adjust the typical dose in the direction ascending or descending to arrange an adequate dose and a Dosing scheme based on individual characteristics and The needs of the patient.

For the treatment of cystic fibrosis, the This composition can be administered to patients by Direct placement in the patient's mouth, or by pre-mixing with foods like applesauce and the like. The dose of Montelukast for cystic fibrosis can be approximately 10 mg per day for an adult and for children about 2 to approximately 5 mg per day. However, the magnitude of the dose may vary with the nature and severity of the state that is being treated and with the patient's age, weight and response individual; a practitioner of ordinary experience in the art will be able to adjust the typical dose upwards or descending to provide an adequate dose and a scheme of dosage based on individual characteristics and patient needs

For the treatment of respiratory syndrome wheezing in children or secondary sibilant to viral bronchiolitis (as respiratory syncytial virus), the present composition may be administered to patients by direct placement in the mouth of the patient, or by prior mixing with food as compote of Apple and the like. The dose of montelukast for these states it can be about 10 mg per day for an adult and for Children from about 2 to about 5 mg per day. Without However, the magnitude of the dose may vary with the nature and the severity of the condition being treated and with age, weight and individual patient response; a practitioner of experience ordinary in the art will be able to adjust the typical dose in ascending or descending direction to arrange an adequate dose and a dosage scheme based on the characteristics individual and patient needs.

The following description of the preparation of the present pharmaceutical composition by way of example only and not should be conceived as a limitation of the scope of the invention in any way.

For the preparation of drug granules, normally the substrate is introduced into a bed granulator fluidized equipped with a top spray nozzle. Be spray an aqueous solution of the binder on the substrate fluidized at a specified flow rate to form granules. The granules are dried and the dried granules are pulverized with a aqueous solution of montelukast sodium. Drug granules The resulting ones are dried and the dried granules are sized to <850 micrometers and then combined with a lubricant by mixing in drum. The lubricated granules are mixed again before being introduced into sachets.

       \ vskip1.000000 \ baselineskip
    

Example one

Preparation of oral granules of montelukast sodium

Mannitol Granulation They are placed in a suitably sized stainless steel vessel with a high shear agitator: USP purified water (102 kg); While stirring at approximately 300 rpm, hydroxypropyl cellulose LF (HPC, 4.16 kg) is added. Mixing is continued at 300 rpm until the hydroxypropyl cellulose is completely dissolved by visual inspection. The solution is allowed to completely froth before being used and the binder solution is used within 72 hours of being manufactured.

It is transferred to a bed granulator fluidized with a 670 l granule cup of mannitol (Pearlitol SD 200, Roquette Freres, 194 kg) and sprayed on the Mannitol in the column the HPC solution previously prepared (106 kg) using the following treatment parameters:

Air volume entry

approx. 2500 scfm

quad

(70.8 m 3 / min)

Air temperature entry

approx. 68 ° C

Air dew point of entry

approx. 12ºC

Air flow atomization

approx. 46 scfm

quad

(1.30 m 3 / min)

Speed of spray

approx. 1310 g / min

       \ vskip1.000000 \ baselineskip
    

After the supply was completed, it dry the product in the column to an end point of ≤ 0.5% LOD (loss on drying), using the following parameters of treatment:

       \ vskip1.000000 \ baselineskip
    

Air volume entry

approx. 2500 scfm

quad

(70.8 m 3 / min)

Air temperature entry

approx. 68 ° C

Air dew point input

approx. 12ºC

Air flow atomization

approx. 30 scfm

quad

(0.85 m 3 / min)

The dried product is extracted in steel drums uncoated stainless.

       \ vskip1.000000 \ baselineskip
    

Preparation of drug solution . It is placed in a suitably sized stainless steel vessel with a USP purified water high shear agitator (49.0 kg, theoretical amount). While stirring at approximately 230 rpm, montelukast sodium (1.70 kg, theoretical amount) is added. Mixing is continued at 230 rpm until the montelukast sodium is completely dissolved by visual inspection. The solution is allowed to completely defoam before being used (the drug solution is used within 24 hours of manufacturing). The amount of drug solution prepared reflects a 2% excess of theory when taking into account spray drying. The amount of coating solution needed can be adjusted if the coating efficiency of the process changes.

Drug coating / drying . The dried mannitol granules (198 kg, theoretical amount) are transferred to a fluidized bed granulator with a 670 granulation cup. Granulation in the column is coated with montelukast solution (50.7 kg, theoretical amount) using the following treatment parameters:

       \ vskip1.000000 \ baselineskip
    

Air volume entry

approx. 2500 scfm

quad

(70.8 m 3 / min)

Air temperature entry

approx. 68 ° C

Air dew point input

approx. 12ºC

Air flow atomization

approx. 35 scfm

quad

(0.99 m 3 / min)

Speed of spray

approx. 1310 g / min

       \ vskip1.000000 \ baselineskip
    

After the supply of the solution, the product is dried in the column to an end point of ≤ 0.5 LOD, using the following treatment parameters:

       \ vskip1.000000 \ baselineskip
    

Air volume entry

approx. 2500 scfm

quad

(70.8 m 3 / min)

Air temperature entry

approx. 68 ° C

Air dew point input

approx. 12ºC

Air flow atomization

approx. 25 scfm

quad

(0.71 m 3 / min)

After drying, the dried granules (200 kg, theoretical amount) are screened through a 20 mesh screen (approximately 850 micrometers). The granulation is stored that passes through the 20 mesh screen (approximately 850 micrometers) in stainless steel container (s) without coat until lubrication.

The amount of drug solution listed reflects 2.14% of the theoretical excess when considering the spray drying. The amount of coating solution necessary can be adjusted if the coating efficiency changes of the procedure Additionally, the actual amount of solution of Powdered drug can be adjusted based on the performance of Dry Mannitol Granulation The amount of drug solution listed above is the maximum amount that could be sprayed (assuming 100% granulation yield of mannitol)

Lubrication The sieved granulation (200 kg, theoretical quantity) and magnesium stearate (previously sieved through a 30 mesh; sieve of approximately 600 microns, 0.500 kg) are added to a 600 l cube. Mix in the 600 l bucket for 10 minutes at approximately 6 rpm. The lubricated combination is extracted in uncoated stainless steel drums.

New mixing The lubricated granulation is introduced into a 600 l bucket and combined in the 600 l bucket for 10 minutes at approximately 6 rpm. The combined again granulation is stored in the closed bucket until the envelope is filled.

Stuffed with envelopes . The 600 l bucket is placed with the previously combined again granulation above the fill line. They are filled in sheet envelopes with a dual helix filling device and the granulation is combined again. Average weights of the fillings: target 0,500 g / envelope. The composition of Singulair® 4 mg oral granule is shown below:

one

Claims (8)

1. A fluid pharmaceutical composition and dispersible, comprising granules comprising a substrate of high pharmaceutically acceptable fluidity coated with montelukast sodium and a pharmaceutically lubricant acceptable. 2. A composition according to claim 1, in which said granules comprise spray dried mannitol coated with montelukast sodium. 3. A composition according to claim 1, in which said granules comprise Pearlitol SD 200 coated with montelukast sodium 4. A composition according to claim 1, in which said granules comprise spray dried mannitol additionally agglomerated with a pharmaceutically binder acceptable and coated with montelukast sodium. 5. A composition according to claim 4, in which said binder is selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose or polyvinylpyrrolidone. 6. A composition according to claim 5, in which said binder is hydroxypropyl cellulose. 7. A composition according to any of the previous claims, wherein said lubricant is stearate  of magnesium or talc. 8. A composition according to claim 7, in which said lubricant is magnesium stearate.